Dipanwita Mitra1, Mohammad H Hasan1, John T Bates1,2, Michael A Bierdeman2, Dallas R Ederer1, Rinkuben C Parmar1, Lauren A Fassero1, Quntao Liang3,4, Hong Qiu5, Vaibhav Tiwari6, Fuming Zhang7, Robert J Linhardt7, Joshua S Sharp3, Lianchun Wang8, Ritesh Tandon1,2,3. 1. Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America. 2. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America. 3. Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, Mississippi, United States of America. 4. College of Biological Science and Engineering, University of Fuzhou, Fujian, China. 5. Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, United States of America. 6. Department of Microbiology and Immunology, Midwestern University, Downers Grove, Illinois, United States of America. 7. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, United States of America. 8. Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States of America.
Abstract
Several enveloped viruses, including herpesviruses attach to host cells by initially interacting with cell surface heparan sulfate (HS) proteoglycans followed by specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions has long been known to result in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide a series of evidence to prove that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) binding and infection. First, purified CMV extracellular virions preferentially bind to sulfated longer chain HS on a glycoarray compared to a variety of unsulfated glycosaminoglycans including unsulfated shorter chain HS. Second, the fraction of glycosaminoglycans (GAG) displaying higher dp and sulfation has a larger impact on CMV titers compared to other fractions. Third, cell lines deficient in specific glucosaminyl sulfotransferases produce significantly reduced CMV titers compared to wild-type cells and virus entry is compromised in these mutant cells. Finally, purified glycoprotein B shows strong binding to heparin, and desulfated heparin analogs compete poorly with heparin for gB binding. Taken together, these results highlight the significance of HS chain length and sulfation patterns in CMV attachment and infectivity.
Several enveloped virusn class="Chemical">es, including herpesviruses attach to host cells by initially interacting with cell surface heparan sulfate (HS) proteoglycans followed by specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions has long been known to result in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide a series of evidence to prove that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) binding andinfection. First, purified CMV extracellular virions preferentially bind to sulfated longer chain HS on a glycoarray compared to a variety of unsulfatedglycosaminoglycans including unsulfated shorter chain HS. Second, the fraction of glycosaminoglycans (GAG) displaying higher dp and sulfation has a larger impact on CMV titers compared to other fractions. Third, cell linesdeficient in specific glucosaminyl sulfotransferases produce significantly reduced CMV titers compared to wild-type cells and virus entry is compromised in these mutant cells. Finally, purified glycoprotein B shows strong binding to heparin, anddesulfatedheparin analogs compete poorly with heparin for gB binding. Taken together, these results highlight the significance of HS chain length and sulfation patterns in CMV attachment and infectivity.
Authors: Ivan Emmanuel Ramos-Martínez; Edgar Ramos-Martínez; René Álvaro Segura-Velázquez; Manuel Saavedra-Montañez; Jacquelynne Brenda Cervantes-Torres; Marco Cerbón; Dulce Papy-Garcia; Edgar Zenteno; José Ivan Sánchez-Betancourt Journal: Int J Mol Sci Date: 2022-08-30 Impact factor: 6.208